RSC Medicinal Chemistry Blog

Stabilised G protein-coupled receptors in structure-based drug design: a case study with adenosine A2A receptor

20 Dec 2012

This review from the MedChemComm New Talent themed issue covers one of the first successful examples of structure-based drug design for stabilised G protein-coupled receptors (GPCRs), focusing on the development of a pre-clinical candidate for the treatment of Parkinson’s disease using StaR® technology.

Stabilised G protein-coupled receptors in structure-based drug design: a case study with adenosine A_2A receptor
Stephen P. Andrews and Benjamin Tehan
DOI: 10.1039/C2MD20164J

Stephen P. Andrews and Benjamin Tehan from Heptares Therapeutics Limited review the role the application of StaR® proteins plays in the discovery and development of new ligands for the adenosine A_2A receptor (A_2AR).

StaR® proteins are GPCRs which have had a small number of point mutations introduced to thermostabilise them. These proteins are stable in detergent micelles and are suitable reagents for use with X-ray crystallography, biophysical screening
techniques and fragment screening. These properties have enabled the application of biophysical screening techniques of ligand–receptor complexes and have facilitated their crystallisation, which has allowed true structure-based drug design on a GPCR to take place for the first time.

This review is separated into two main parts:

1) Applications of stabilised GPCRs
– Describing the thermostabilisation process for generating StaR® proteins and, using A_2AR as an example, considers the implications that this has on receptor conformation.

2) Structure-based drug design with StaRs®
– Discussing how the application of techniques covered in the first part of the review aided in the optimisation of a hit A2AR antagonist which was identified by virtual screening of experimentally enabled homology models.

Read the complete review here…

and find more articles from our New Talent themed issue here…

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MedChemComm prizes at 6th Biological and Medicinal Chemistry Symposium

18 Dec 2012

By Richard Kelly.

Congratulations to Mark Rackham and Kerya Long, winners of the MedChemComm prizes at the 6^th Biological and Medicinal Chemistry Symposium.

Mark, who is part of Professor Robin Leatherbarrow’s group at Imperial College, London, received the prize for Best Oral Contribution for his presentation entitled ‘Design and Synthesis of Highly Potent Inhibitors of Plasmodium falciparum N-Myristoyltranferase as a promising treatment for malaria’.

Oral contribution prize winner Mark Rackham with BMCS Committee member Dave Alker

Kerya, from Dr Andrew Wilson’s group at University of Leeds, was awarded Best Poster Contribution for ‘Development of synthetic α-helix mimetics as potent anticancer agents’. Both winners receive a year’s subscription to MedChemComm.

Poster contribution winner Kerya Long with Dave Alker

The symposium, organised by the RSC’s Biological & Medicinal Chemistry interest group, was held at the University of Cambridge on 14^th December 2012.

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Helping the fight against flu

18 Dec 2012

By James Anson.

Highlighting a HOT MedChemComm article being featured in Chemistry World

With up to five million cases of the acute respiratory illness influenza leading to half a million deaths each year worldwide, the search for better treatments is important. Scientists from Australia and the US have developed a synthesis for a drug that gives higher yields and antiviral activity than currently used commercial drugs, such as Relenza (zanamivir) and Tamiflu (oseltamivir), they claim.

Although existing dimeric zanamivir compounds show significant therapeutic potential, the currently used synthesis method only produces the compounds in moderate yields. Benjamin Fraser and co-workers at the Australian Nuclear Science and Technology Organisation have designed a higher-yielding synthesis route, which can also prepare the dimers with new linker functionality.

The group prepared the new class of zanamivir dimers by using a known cycloaddition reaction that improved the coupling yields and allowed rapid optimisation of the antiviral activity as a function of the linker length. The dimers synthesised are among the most effective inhibitors of influenza to date, being up to 3000 times more potent than zanamivir. This potency may be because the dimers work by a dual mechanism: they inhibit neuraminidase (an enzyme on the virus’ surface and a target in influenza treatments) and their aggregation is enhanced.

Although vaccination programs reduce the risk of an epidemic influenza outbreak, there is still a need for antiviral drugs © Shutterstock

Fraser comments that the dimers are still at the research stage, so a significant amount of further testing is required before the drugs can be ready for human use. The group hopes to radiolabel the compounds in the future so the bio-distribution, metabolism and retention time in the lungs can be measured. Fraser also mentions that it may also be possible to obtain even greater antiviral activity by developing high order multimers, including trimers and tetramers of zanamivir, as each neuraminidase receptor on the virus has four active sites.

Although neither approach used by the group is new, comments Hans Streicher at the University of Sussex, UK, the study adds ‘valuable information regarding the optimal distance’ between the inhibitor moieties, and will thus aid the development of a new generation of anti-influenza drugs.

Story first published in Chemistry World

And read the full MedChemComm paper for free for 4 weeks here:

Synthesis of 1,4-triazole linked zanamivir dimers as highly potent inhibitors of influenza A and B
Benjamin H. Fraser, Stephanie Hamilton, Anwen M. Krause-Heuer, Philip J. Wright, Ivan Greguric, Simon P. Tucker, Alistair G. Draffan, Valery V. Fokin and K. Barry Sharpless

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Challenges in Chemical Biology (ISACS11) – Call for Abstracts

14 Dec 2012

By James Anson.

We are proud to announce that the significant International Symposia on Advancing the Chemical Sciences (ISACS) series will return in 2013 to include Challenges in Chemical Biology (ISACS11) on 23-26 July 2013 in Boston, UK.

Abstracts are now invited for this event so submit today and take advantage of this exceptional opportunity to present your work alongside scientists from across the globe.

For details of speakers and conferences themes, please visit the dedicated website.

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Drug discovery: on the origins of drug polypharmacology – a review

28 Nov 2012

By Marie Cote, Deputy Editor.

‘The ability of many drugs, unintended most often, to interact with multiple proteins is commonly referred to as polypharmacology. Could this be a reminiscent chemical signature of early protein evolution?’ asks Jordi Mestres.

In this review article, Xavier Jalencas and Jordi Mestres (Chemogenomics Laboratory, Hospital del Mar Research Institute, Barcelona) explore the origins of drug polypharmacology and provide clues as to why most drugs hit multiple targets. Covering both the chemical (including molecular properties and fragment composition of the drug themselves) and the biological sources of polypharmacology (describing target phylogeny and binding site similarity), the article also provides some direct key implications of polypharmacology for drug discovery, while questioning whether this multitarget ability could have come from adaptative mechanisms…

Take this fascinating journey and read the full review today!

On the origins of drug polypharmacology
Xavier Jalencas and Jordi Mestres
Med. Chem. Commun, 2013, Advance Article
DOI:10.1039/C2MD20242E

This article is part of MedChemComm’s New Talent themed issue

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MedChemComm Emerging Investigator Lectureship award – nominations now open!

26 Nov 2012

By Aliya Anwar.

Voting for the MedChemComm Emerging Investigator Lectureship is now open. This annual Lectureship recognises an emerging scientist who has made a significant contribution to medicinal chemistry or a related field in the early part of their independent career.

To make a nomination, please contact the MedChemComm Editorial Office with both the name and affiliation of the person you are nominating along with a brief description of why they should be considered. All members of the community are eligible to vote; however, nominated individuals must have published their work in MedChemComm in order to be eligible for entry. Nominees must also have completed their PhD on or after the 31st December 2002.

Closing date for Nominations is the 31^st December 2012

The decision to award the Lectureship will be made by a panel of MedChemComm Editorial Board members. The receipient will receive a contribution towards speaking at a conference of their choice.

This year’s winner Dr Patrick Gunning, (University of Toronto, Canada) was presented with the Lectureship due to his prominent work into the investigation and manipulation of protein function. He will be presenting a lecture at an international conference in 2013.

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Spinks Symposium 2013: Regenerative Medicine

26 Nov 2012

By Marie Cote, Deputy Editor.

28 January 2013

Chemistry Centre, Burlington House, London

The therapeutic promise of regenerative medicine, as a way to restore aging or damaged tissues and organs, is one of the most exciting areas of medicines research. With the proportion of older people increasing, degenerative and chronic diseases are a major challenge. To move forward, the chemical sciences have a vital role to play in understanding

disease mechanisms
signalling of stem cells
cellular differentiation
new methodologies for surface modification

The 2013 Spinks Symposium will explore the critical issues that underpin developments in regenerative medicine and provide a clear understanding of the challenges involved in translating research outputs into application. Particular emphasis will be put on how medicinal chemistry/chemical biology research might provide a springboard to therapeutic development. Researchers from industry, academia and the wider health sciences sectors will join together for this stimulating workshop, including oral presentations discussion groups, flash presentations and a comprehensive poster session.

How can I get involved?

Abstracts for the poster programme are now invited. Take full advantage of this exceptional opportunity to present your work and submit before Friday 21st December.
Registration is also open and if you would like to benefit from the early bird rates be sure to secure your place before Friday 21st December

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MedChemComm issue 12: featuring macrocyclization efficiency & transdermal insulin delivery

22 Nov 2012

By James Anson.

Welcome to issue 12 of MedChemComm, the last of 2012. This month we have 10 concise articles and 1 review for you to devour.

On the front cover:

Is this review from our collection on ‘The space in-between small molecules and biologicals’ by James C. Collins and Keith James. Collins and James present a critical analysis of macrocyclization reactions published over the past three years, and based on this propose a ‘macrocyclization efficiency index, Emac,’ which would allow the community to determine the true efficiency of a macrocyclization reaction.

Emac – a comparative index for the assessment of macrocyclization efficiency
James C. Collins and Keith James
DOI: 10.1039/C2MD20176C

On the inside cover:

Is this concise article from Masahiro Goto and colleagues who present their investigations into developing a unique, through the skin, protein-delivery system based on a solid-in-oil nanodispersion that utilizes an oil-based vehicle of proteins.

Transdermal delivery of insulin using a solid-in-oil nanodispersion enhanced by arginine-rich peptides
Yoshiro Tahara, Shota Honda, Noriho Kamiya and Masahiro Goto
DOI: 10.1039/C2MD20059G

Remember both of these articles are free to access for the next 6 weeks!

Get your hands on the last issue of 2012 today.

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Emac – a comparative index for the assessment of macrocyclization efficiency

19 Nov 2012

By James Anson.

New drug design strategies are required that deliver agents possessing ‘small molecule properties’ but that also possess the ability to disrupt interactions between large protein surfaces in a similar manner to current protein-based therapeutics.

Macrocycle-based drug design represents a new and compelling strategy that could fulfil this need; however typical high-dilution macrocyclisation conditions are inefficient and impractical in a pharmaceutical setting from cost, capacity and green chemistry perspectives.

In this review James C. Collins and Keith James from the Scripps Research Institute critically analyse macrocyclization reactions published over the last three years. Based upon on this analysis, and first-hand experience of macrocyclization, Collins and James propose a macrocyclization efficiency index, Emac, as a means of determining the true efficiency of a macrocyclization reaction.

Emac takes into account both reaction yield and concentration, which Collins & James state addresses the key factors that determine the practicality of using a given reaction in a drug discovery context. In other words, the Emac for a reaction indicates the likelihood of being able to conduct the reaction on a sufficiently large scale whilst remaining resource efficient.

This index also allows comparison of a large number of literature macrocyclization reactions and identifies those which deliver the powerful combination of high yield and high practicality. Collins and James hope that those who are actively engaged within the macrocyclization community will calculate the Emac for their reactions and report it in their publications, allowing the synthesis community to place the reaction within the context of the framework they outline in the review.

To read more about this index download the review today.

Emac – a comparative index for the assessment of macrocyclization efficiency
James C. Collins and Keith James
DOI: 10.1039/C2MD20176C
From the collection: The space in-between small molecules and biologicals

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Chemical biology and medicinal: Optimising compounds for diabetes treatment

12 Nov 2012

By Aliya Anwar.

Scientists have optimised a series of compounds that have the potential to treat diabetes and obesity.
The drug candidates work by inhibiting the enzyme diacylglycerol acetyl transferase 1, which is responsible for catalysing the production of triglycerides. Excessive levels of triglycerides contribute to metabolic syndrome, which increases risk of diabetes, heart disease and stroke. Previous drug inhibitors have been unsuccessful in clinical trials due to low solubility. The optimised compounds are highly soluble and exhibit excellent potency for their target.

Graphical Abstract

Optimisation of biphenyl acetic acid inhibitors of diacylglycerol acetyl transferase 1 – the discovery of AZD2353
Michael J. Waring, Alan M. Birch, Susan Birtles, Linda K. Buckett, Roger J. Butlin, Leonie Campbell, Pablo Morentin Gutierrez, Paul D. Kemmitt, Andrew G. Leach, Philip A. MacFaul, Charles O’Donnell and Andrew V. Turnbull
Med. Chem. Commun., DOI: 10.1039/C2MD20190A

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RSC Medicinal Chemistry Blog

Stabilised G protein-coupled receptors in structure-based drug design: a case study with adenosine A2A receptor

MedChemComm prizes at 6th Biological and Medicinal Chemistry Symposium

Helping the fight against flu

Challenges in Chemical Biology (ISACS11) – Call for Abstracts

Drug discovery: on the origins of drug polypharmacology – a review

MedChemComm Emerging Investigator Lectureship award – nominations now open!

Spinks Symposium 2013: Regenerative Medicine

MedChemComm issue 12: featuring macrocyclization efficiency & transdermal insulin delivery

Emac – a comparative index for the assessment of macrocyclization efficiency

Chemical biology and medicinal: Optimising compounds for diabetes treatment

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